The NEIGHBORHOOD: POAG Heritable Overall Operational Database

描述（由申请人提供）：原发性开角型青光眼（POAG）是全球失明的重要原因。POAG的病因尚不清楚，无法进行一级预防。目前的治疗可以减缓但不能治愈这种进行性神经病变。我们研究的总体目标是阐明原发性开角型青光眼（POAG）的发病机制，为实施有效的筛查和预防策略以及开发新的治疗方法提供可能。虽然POAG具有显著的遗传性，但最近使用中等样本量的全基因组关联研究仅确定了少数具有中等效应的POAG相关基因。这些结果表明，需要具有明确表型的大型数据集来充分描述POAG的遗传结构。该提案将有效地利用现有的数据集来创建一个大样本，用于研究POAG的遗传决定因素，主要重点是识别与POAG相关的定量内表型有关的基因，杯盘比（CDR）。新出现的数据表明，CDR，即使是主观确定的，也是一个重要的结果，为POAG的发病机制提供了有价值的见解。此前，我们组建了两个合作联盟，分别为GWA研究贡献了3517例POAG病例和3631例对照，一个是NEIGHBOR联盟（NEI青光眼人类遗传合作），另一个是GLAUGEN研究（青光眼遗传学）。该提案的直接目标是：1)扩展NEIGHBOR和GLAUGEN联盟，创建NEIGHBORHOOD （NEIGHBOR Heritable Overall Operational Database）联盟和数据库，该数据库将包括4,652例POAG病例、16,909例CDR受试者和42,486例对照的统一基因型和表型数据；2)使用该增强数据集进行meta分析，以确定影响CDR的新基因，以及导致POAG的基因。此外，该建议将为未来研究CDR和POAG的其他POAG相关性状以及基因-基因和基因-环境相互作用奠定基础。

DESCRIPTION (provided by applicant): Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary open-angle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. While POAG has a significant heritability, recent genome-wide association studies using moderate sample sizes have only identified a few POAG-related genes with modest effect sizes. These results suggest that large datasets with well-defined phenotypes are needed to fully delineate the genetic architecture of POAG. This proposal will efficiently use existing datasets to create a large sample useful for investigation o genetic determinants of POAG, with a primary focus of identifying genes contributing to the POAG-related quantitative endophenotype, cup-to-disc ratio (CDR). Emerging data suggests that CDR, even when subjectively ascertained, is an important outcome providing valuable insights into the pathogenesis of POAG. Previously we formed two collaborative consortia contributing 3,517 POAG cases and 3,631 controls for GWA studies, the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) and the GLAUGEN study (Glaucoma Genetics). The immediate goals of this proposal are: 1) expand the NEIGHBOR and GLAUGEN consortia to create the NEIGHBORHOOD (NEIGHBOR Heritable Overall Operational Database) consortium and database, which will include harmonized genotype and phenotype data for a total of 4,652 POAG cases, 16,909 subjects with CDR and 42,486 controls~ and, 2) use this enhanced dataset to perform meta-analyses to identify novel genes influencing CDR, as well as genes that contribute to POAG. Additionally, this proposal will form the basis of future studies of other POAG related traits and gene-gene and gene-environment interactions for CDR and POAG. PUBLIC HEALTH RELEVANCE: Primary open angle glaucoma (POAG) causes permanent loss of vision and is a condition of public health significance worldwide, affecting millions of people. The etiology of POAG is poorly understood and effective means of primary prevention and curative therapies are not available. In this proposal, our collaborative consortium will develop an operational database housing phenotype and genotype information for over 4600 POAG cases, 16,000 individuals with data for the heritable POAG endophenotype cup-to-disc ratio (CDR), and 42,000 controls that can be used to identify risk factors for POAG with the ultimate goal of elucidating the molecular pathogenesis of POAG making it possible to implement effective screening and prevention strategies and to develop novel therapies.